Novel aminal dione compounds and their derivatives can open potassium channels and are useful for treating a variety of medical conditions.
Potassium channels play an important role in regulating cell membrane excitability. When the potassium channels open, changes in the electrical potential across the cell membrane occur and result in a more polarized state. A number of diseases or conditions may be treated with therapeutic agents that open potassium channels; see for example (Lawson, Pharmacol. Ther., v. 70, pp. 39-63 (1996)); (Gehlert et al., Prog. Neuro-Psychopharmacol and Biol. Psychiat., v. 18, pp. 1093-1102 (1994)); (Gopalakrishnan et al., Drug Development Research, v. 28, pp. 95-127 (1993)); (Freedman et al., The Neuroscientist, v. 2, pp. 145-152 (1996)); (Nurse et al., Br. J. Urol., v. 68 pp. 27-31 (1991)), (Howe et al., J. Pharmacol. Exp. Ther., v. 274 pp. 884-890 (1995)); (Spanswick et al.; Nature, v. 390 pp. 521-25 (Dec. 4, 1997)); (Dompeling Vasa. Supplementum (1992) 3434); (WO9932495); (Grover, J Mol Cell Cardiol. (2000) 32, 677), and (Buchheit, Pulmonary Pharmacology and Therapeutics (1999) 12, 103). Such diseases or conditions include asthma, epilepsy, male sexual dysfunction, female sexual dysfunction, pain, bladder overactivity, stroke, diseases associated with decreased skeletal blood flow such as Raynaud""s phenomenon and intermittent claudication, eating disorders, functional bowel disorders, neurodegeneration, benign prostatic hyperplasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, coronary artery disease, angina and ischemia.
Bladder overactivity is a condition associated with the spontaneous, uncontrolled contractions of the bladder smooth muscle. Bladder overactivity thus is associated with sensations of urgency, urinary incontinence, pollakiuria, bladder instability, nocturia, bladder hyerreflexia, and enuresis (Resnick, The Lancet (1995) 346, 94-99; Hampel, Urology (1997) 50 (Suppl 6A), 4-14; Bosch, BJU International (1999) 83 (Suppl 2), 7-9Potassium channel openers (KCOs) act as smooth muscle relaxants. Because bladder overactivity and urinary incontinence can result from the spontaneous, uncontrolled contractions of the smooth muscle of the bladder, the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle may provide a method to ameliorate or prevent bladder overactivity, pollakiuria, bladder instability, nocturia, bladder hyperreflexia, urinary incontinence, and enuresis (Andersson, Urology (1997) 50 (Suppl 6A), 74-84; Lawson, Pharmacol. Ther., (1996) 70, 3963; Nurse., Br. J. Urol., (1991) 68, 27-31; Howe, J. Pharmacol. Exp. Ther., (1995)274, 884-890; Gopalakishnan, Drug Development Research, (1993) 28, 95-127).
The irritative symptoms of BPH (urgency, frequency, nocturia and urge incontinence) have been shown to be correlated to bladder instability (Pandita, The J. of Urology (1999) 162, 943). Therefore the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle may provide a method to ameliorate or prevent the symptoms associated with BPH. (Andersson, Prostate (1997) 30: 202-215).
The excitability of corpus cavernosum smooth muscle cells is important in the male erectile process. The relaxation of corporal smooth muscle cells allows arterial blood to build up under pressure in the erectile tissue of the penis leading to erection (Andersson, Pharmacological Reviews (1993) 45, 253). Potassium channels play a significant role in modulating human corporal smooth muscle tone, and thus, erectile capacity. By patch clamp technique, potassium channels have been characterized in human corporal smooth muscle cells (Lee, Int. J. Impot. Res. (1999) 11(4),179-188). Potassium channel openers are smooth muscle relaxants and have been shown to relax corpus cavernosal smooth muscle and induce erections (Andersson, Pharmacological Reviews (1993) 45, 253; Lawson, Pharmacol. Ther., (1996) 70, 39-63, Vick, J. Urol. (2000) 163: 202). Potassium channel openers therefore may have utility in the treatment of male sexual dysfunctions such as male erectile dysfunction, impotence and premature ejaculation.
The sexual response in women is classified into four stages: excitement, plateau, orgasm and resolution. Sexual arousal and excitement increase blood flow to the genital area, and lubrication of the vagina as a result of plasma transudation. Topical application of KCOs like minoxidil and nicorandil have been shown to increase clitoral blood flow (Kim, et al., J. Urol. (2000) 163 (4): 240). KCOs may be effective for the treatment of female sexual dysfunction including clitoral erectile insufficiency, vaginismus and vaginal engorgement (Goldstein and Berman., Int. J. Impotence Res. (1998) 10:S84-S90), as KCOs can increase blood flow to female sexual organs.
Potassium channel openers may have utility as tocolytic agents to inhibit uterine Contractions to delay or prevent premature parturition in individuals or to slow or arrest delivery for brief periods to undertake other therapeutic measures (Sanborn, Semin. Perinatol. (1995) 19, 31-40, Morrison, Am. J. Obstet. Gynecol. (1993) 169(5), 1277-85). Potassium channel openers also inhibit contractile responses of human uterus and intrauterine vasculature. This combined effect would suggest the potential use of KCOs for dysmenhorrea (Kostrzewska, Acta Obstet. Gynecol. Scand. (1996) 75(10), 886-91). Potassium channel openers relax uterine smooth muscle and intrauterine vasculature and therefore may have utility in the treatment of premature labor and dysmenorrhoea (Lawson, Pharmacol. Ther., (1996) 70, 39-63).
Potassium channel openers relax gastrointestinal smooth tissues and therefore may be useful in the treatment of functional bowel disorders such as irritable bowel syndrome (Lawson, Pharmacol. Ther., (1996) 70, 39-63).
Potassium channel openers relax airway smooth muscle and induce bronchodilation. Therefore potassium channel openers may be useful in the treatment of asthma and airways hyperreactivity (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Buchheit, Pulmonary Pharmacology and Therapeutics (1999) 12, 103; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
Neuronal hyperpolarization can produce analgesic effects. The opening of potassium channels by potassium channel openers and resultant hyperpolarization in the membrane of target neurons is a key mechanism in the effect of opioids. The peripheral antinociceptive effect of morphine results from activation of ATP-sensitive potassium channels, which causes hyperpolarization of peripheral terminals of primary afferents, leading to a decrease in action potential generation (Rodrigues, Br. J. Pharmacol. (2000) 129(1), 11-04). Opening of KATP channels by potassium channel openers plays an important role in the antinociception mediated by alpha-2 adrenoceptors and mu opioid receptors. KCOs can potentiate the analgesic action of both morphine and dexmedetomidine via an activation of KATP channels at the spinal cord level (Vergoni, Life Sci. (1992) 50(16), PL135-8; Asano, Anesth. Analg. (2000) 90(5), 1146-51). Thus, potassium channel openers can hyperpolarize neuronal cells and have shown analgesic effects. Potassium channel openers therefore may be usefull as analgesics in the treatment of various pain states including but not limited to migraine and dyspareunia (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., (1994) 18, 1093-1102).
Epilepsy results from the propagation of nonphysiologic electrical impulses. Potassium channel openers hyperpolanize neuronal cells and lead to a decrease in cellular excitability and have demonstrated antiepileptic effects. Therefore potassium channel openers may be useful in the treatment of epilepsy (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127, Gehlert, Prog. Neuro-Psychopharmacol. and Biol. Psychiat, (1994) 18, 1093-1102).
Neuronal cell depolarization can lead to excitotoxicity and neuronal cell death. When this occurs as a result of acute ischemic conditions, it can lead to stroke. Long-term neurodegeneration can bring about conditions such as Alzheimer""s and Parkinson""s diseases. Potassium channel openers can hyperpolarize neuronal cells and lead to a decrease in cellular excitability. Activation of potassium channels has been shown to enhance neuronal survival. Therefore potassium channel openers may have utility as neuroprotectants in the treatment of neurodegenerative conditions and diseases such as cerebral ischemia, stroke, Alzheimer""s disease and Parkinson""s disease (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol and Biol. Psychiat., (1994) 18, 1093-1102; Freedman, The Neuroscientist (1996) 2, 145).
Potassium channel openers may have utility in the treatment of diseases or conditions associated with decreased skeletal muscle blood flow such as Raynaud""s syndrome and intermittent claudication (Lawson, Pharmacol. Ther., (1996) 70, 39-63, Gopalakiishnan, Drug Development Research, (1993) 28, 95-127; Dompeling Vasa. Supplementum (1992) 3434; and WO9932495).
Potassium channel openers may be useful in the treatment of eating disorders such as obesity (Spanswick, Nature, (1997) 390, 521-25; Freedman, The Neuroscientist (1996) 2, 145).
Potassium channel openers have been shown to promote hair growth therefore potassium channel openers have utility in the treatment of hair loss and baldness also known as alopecia (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
Potassium channel openers possess cardioprotective effects against myocardial injury during ischemia and reperfusion. (Garlid, Circ. Res. (1997) 81(6), 1072-82). Therefore, potassium channel openers may be useful in the treatment of heart diseases (Lawson, Pharmacol. Ther., (1996) 70,39-63; Grover, J. Mol. Cell Cardiol. (2000) 32, 677).
Potassium channel openers, by hyperpolarization of smooth muscle membranes, can exert vasodilation of the collateral circulation of the coronary vasculature leading to increase blood flow to ischemic areas and could be useful for the coronary artery disease (Lawson, Pharmacol. Ther:, (1996) 70,39-63; Gopalakrishnan, Drug Development Research, (1993) 28,.95-127).
U.S. Pat. No. 3,636,105 discloses a group of 1-fluoroacetylamino-2,2,2-trichloroethyl urea rodenticide agents. U.S. Pat. No. 4,146,646 discloses a group of bis-amides as fungicide agents. ZA 695324 discloses a group of thioureas useful as insecticide, acaricidal, and rodenticide agents. U.S. Pat. No. 5,397,790 discloses a group of substituted isoquinolinyl-1,2-diaminocyclobutene-3,4-diones as smooth muscle relaxants. U.S. Pat. No. 5,401,753 and U.S. Pat. No. 5,403,854 disclose groups of substituted N-heteroaryl-1,2-diaminocyclobutene-3,4-diones as smooth muscle relaxants. U.S. Pat. No. 5,403,853, U.S. Pat. No. 5,466,712, and WO 98/33763 disclose groups of substituted N-aryl-1,2-diaminocyclobutene-3,4-diones. U.S. Pat. No. 5,464,867 and U.S. Pat. No. 5,512,585 disclose groups of substituted N-heteroaryl-Nxe2x80x2-alkyl-1,2-diaminocyclobutene-3,4-diones as smooth muscle relaxants. U.S. Pat. No. 5,506,252 and WO 96/15103 disclose groups of substituted N-aryl- and N-heteroaryl-1,2-diaminocyclobutene-3,4-diones as smooth muscle relaxants. U.S. Pat. No. 5,750,574 discloses a group of substituted fluorinated N-arylmethylamino derivatives of cyclobutene-3,4-dione as agents for reducing the adverse effects of smooth muscle contractions. U.S. Pat. No. 5,763,474, U.S. Pat. No. 5,780,505, U.S. Pat. No. 5,846,999, and WO 98/02413 disclose groups of substituted N-arylmethylamino derivatives of cyclobutene-3,4-diones as smooth muscle relaxants U.S. Pat. No. 5,872,139 and WO 97/48682 disclose groups of N-heterocyclylmethylamino derivatives of cyclobutene-3,4-dione as agents for reducing the adverse effects of smooth muscle contractions. U.S. Pat. No. 6,166,050 discloses a group of amino(heterocyclylanilino)-3-cyclobutene-1,2-diones as inhibitors of leukocyte adhesion mediated by VLA-4. WO 94/29277 discloses a group of 3,4-diaminocyclobutene-1,2-diones as inhibitors of cGMP phosphodiesterase. WO 00/51973 and WO 00/63160 discloses groups of substituted N-(cyclohexylmethyl)amino-3 -cyclobutene-1,2-diones as inhibitors phosphodiesterase V. WO 00/73260 discloses a group of 3,4-diamino-3-cyclobutene-1,2-diones as inhibitors of leukocyte adhesion mediated by VLA-4.
Compounds of the present invention are novel, hyperpolarize cell membranes, open potassium channels, relax smooth muscle cells, inhibit bladder contractions and may be useful for treating diseases that can be ameliorated by opening potassium channels.
In its principle embodiment, the present invention discloses compounds having formula (I) 
or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of 
X is selected from the group consisting of CH2, O and N(Z);
Z is selected from the group consisting of hydrogen and alkyl;
R1 is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl;
R2, R3 and R4 are independently selected from hydrogen and alkyl;
R5 is selected from aryl, arylalkenyl, arylalkyl, aryloxyalkyl, heterocycle and heterocyclealkyl,
R6 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl(halo)alkyl, alkoxy(halo)alkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyl(halo)alkyl, alkylcarbonyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylthioalkyl, alkynyl, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alkyl, aryloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy, carboxyalkyl, carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxyalkyl, cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl, haloalkynyl, heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl, sulfamylalkyl, sulfamyl(halo)alkyl, (NR9R10)alkyl, (NR9R10)carbonyl, and (NR9R10)carbonylalkyl;
R7 is selected from hydrogen, haloalkyl, and lower alkyl; or
R6 and R7 taken together with the carbon atom to which they are attached, together form a 5 or 6 membered carbocyclic ring wherein the 5 or 6 membered carbocyclic ring is optionally substituted with 1 or 2 substituents independently selected from alkenyl, alkoxy, alkyl, alkynyl, halogen, haloalkoxy, and haloalkyl;
R9 and R10 are independently selected from hydrogen, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof
All patents, patent applications, and literature references cited in the specification are herein incorporated by reference in their entirety.
In its principle embodiment, the present invention discloses compounds having formula (I) 
or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of 
X is selected from the group consisting of CH2, O and N(Z);
Z is selected from the group consisting of hydrogen and alkyl;
R1 is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl;
R2, R3 and R4 are independently selected from hydrogen and alkyl;
R5 is selected from aryl, arylalkyl, aryloxyalkyl, heterocycle and heterocyclealkyl;
R6 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl(halo)alkyl, alkoxy(halo)alkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyl(halo)alkyl, alkylcarbonyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylthioalkyl, alkynyl, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alkyl, aryloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy, carboxyalkyl, carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxyalkyl, cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl, haloalkynyl, heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl, sulfamylalkyl, sulfamyl(halo)alkyl, (NR9R10)alkyl, (NR9R10)carbonyl and (NR9R10)carbonylalkyl;
R7 is selected from hydrogen, haloalkyl, and lower alkyl; or
R6 and R7 taken together with the carbon atom to which they are attached, together form a 5 or 6 membered carbocyclic ring wherein the 5 or 6 membered carbocyclic ring is optionally substituted with 1 or 2 substituents independently selected from alkenyl, alkoxy, alkyl, alkynyl, halogen, haloalkoxy, and haloalkyl;
R9 and R10 are independently selected from hydrogen, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl.
In another embodiment of the present invention, compounds have formula (I) wherein A is selected from 
R1, R2, R3, R4, R5, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) 
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle; R5 is aryl; and R2, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is selected from optionally substituted pyridinyl and optionally substituted pyrazinyl; R5 is aryl wherein said aryl is optionally substituted phenyl; and R2, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is selected from optionally substituted pyridinyl and optionally substituted pyrazinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is selected from hydrogen and alkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is selected from arylalkyl and heterocyclealkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl and the heterocycle portion of said heterocyclealkyl is optionally substituted pyridinyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is haloalkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl;, R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, cyanoalkyl and cycloalkylalkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein heterocycle is optionally substituted pyridinyl; R5 is aryl wherein aryl is selected from optionally substituted naphthyl and optionally substituted fluorenyl; and R2, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is aryl wherein aryl is selected from optionally substituted naphthyl and optionally substituted fluorenyl; R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen, R3 is hydrogen; R4 is hydrogen; R5 is aryl wherein aryl is selected from optionally substituted naphthyl and optionally substituted fluorenyl 1; R6 is alkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II) wherein R1 is aryl; R5 is aryl; and R2, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) wherein R1 is aryl wherein said aryl is optionally substituted phenyl; R5 is aryl wherein said aryl is optionally substituted phenyl; and R2; R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) wherein R1 is aryl wherein said aryl is optionally substituted phenyl R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II) wherein R1 is aryl wherein said aryl is optionally substituted phenyl; R2 is hydrogen, R3 is hydrogen; R4 is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is alkyl; and R7 is hydrogen
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle; R5 is arylalkyl; and R2, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R5 is selected from arylalkyl, arylalkenyl and aryloxyalkyl wherein the aryl portion of said arylalkyl, arylalkenyl, and aryloxyalkyl is optionally substituted phenyl; and R2, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen, R5 is selected from arylalkyl, arylalkenyl and aryloxyalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, the aryl portion of said arylalkenyl is optionally substituted phenyl and the aryl portion of said aryloxyalkyl is optionally substituted phenyl; R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl, R2 is hydrogen; R3 is hydrogen; R4 is hydrogen, R5 is selected from arylalkyl, arylalkenyl and aryloxyalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, the aryl portion of said arylalkenyl is optionally substituted phenyl and the aryl portion of said aryloxyalkyl is optionally substituted phenyl; R6 is selected from alkyl and arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle, R5 is heterocyclealkyl; and R2, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R5 is heterocyclealkyl wherein the heterocycle portion of said heterocyclealkyl is optionally substituted pyridinyl; and R2, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is heterocyclealkyl wherein the heterocycle portion of said heterocyclealkyl is optionally substituted pyridinyl; R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl, and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl, R2 is hydrogen; R3 is hydrogen, R4 is hydrogen, R5 is heterocyclealkyl wherein the heterocycle portion of said heterocyclealkyl is optionally substituted pyridinyl; R6 is alkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle; R5 is heterocycle; and R2, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R5 is heterocycle wherein said heterocycle is selected from optionally substituted pyridinyl, optionally substituted thienyl and optionally substituted furyl; and R2, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is heterocycle wherein said heterocycle is selected from optionally substituted pyridinyl, optionally substituted thienyl and optionally substituted furyl; R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is heterocycle wherein said heterocycle is selected from optionally substituted pyridinyl, optionally substituted thienyl and optionally substituted furyl; R6 is alkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (III) 
or a pharmaceutically acceptable salt therof, wherein R1, R2, R3, R4, R5, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (III) wherein R1 is heterocycle; R5 is aryl; and R2, R3, R4, R6 and R7 are as defined in formula
In another embodiment of the present invention, compounds have formula (III) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R5 is aryl wherein said aryl is optionally substituted phenyl; and R2, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (III) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (III) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is alkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (IV) 
or a pharmaceutically acceptable salt therof, wherein R1, R2, R3, R4, R5, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (IV) wherein R1 is heterocycle; R5 is aryl; and R2, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (IV) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R5 is aryl wherein said aryl is optionally substituted phenyl; and R2, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (IV) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen R4 is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (IV) wherein R1 is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is alkyl; and R7 is hydrogen.
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I-IV or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a method of treating male sexual dysfunction including, but not limited to, male erectile dysfunction and premature ejaculation, comprising administering a therapeutically effective amount of a compound of formula I-IV or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Another embodiment of the present invention relates to a method of treating female sexual dysfunction including, but not limited to, female anorgasmia, clitoral erectile insufficiency, vaginal engorgement, dyspareunia, and vaginismus comprising administering a therapeutically effective amount of a compound of formula I-IV or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Another embodiment of the present invention relates to a method of treating asthma, epilepsy, Raynaud""s syndrome, intermittent claudication, migraine, pain, bladder overactivity, pollakiuria, bladder instability, nocturia, bladder hyperreflexia, eating disorders, urinary incontinence, enuresis, functional bowel disorders, neurodegeneration, benign prostatic byperplasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, and ischemia comprising administering a therapeutically effective amount of a compound of formula I-IV or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof
Another embodiment of the present invention relates to a process of preparing a compound of formula (V) 
wherein R1 is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl;
R2, R3 and R4 are independently selected from hydrogen and alkyl;
R5 is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl;
R6 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl(halo)alkyl, alkoxy(halo)alkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyl(halo)alkyl, alkylcarbonyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylthioalkyl, alkynyl, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alkyl, aryloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy, carboxyalkyl, carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxyalkyl, cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl, haloalkynyl, heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl, sulfamylalkyl, sulfamyl(halo)alkyl, (NR9R10)alkyl, (NR9R10)carbonyl and (NR9R10)carbonylalkyl; and
R9 and R10 are independently selected from hydrogen, alkoxysulfonyl, alky, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl;
the process comprising:
(a) reacting an aldehyde of formula (VI) 
with three components, an amide of formula (VII) 
1H-benzotriazole-polystyrene resin and an acid in a first solvent at about 50xc2x0 C. to about 80xc2x0 C., wherein R4, R5 and R6 are as defined above;
(b) reacting the product of step (a) with a base and a compound of formula (VI) 
in a second solvent wherein R1, R2 and R3 are as defined above to provide a compound of formula (V).
In another embodiment of the present invention is disclosed a process for preparing a compound of formula (V) using an acid selected from para-toluenesulfonic acid monohydrate and acetic acid.
In another embodiment of the present invention is disclosed a process for preparing a compound of formula (V) using a first solvent selected from 1,4-dioxane, 2-methoxyethanol, tetrahydrofuran, trimethyl orthoformate and mixtures thereof
In another embodiment of the present invention is disclosed a process for preparing a compound of formula (V) using a first solvent selected from tetrahydrofuran:2-methoxyethanol in about a (1:1) ratio, tetrahydrofuran:trimethyl orthoformate in about a (1:1) ratio and 1,4-dioxane:trimethyl orthoformate in about a (1:0.3) to (1:3) ratio.
In another embodiment of the present invention is disclosed a process for preparing a compound of formula (V) wherein step (a) is conducted for a period of about 12 hours to about 48 hours.
In another embodiment of the present invention is disclosed a process for preparing a compound of formula (V) using a base selected from cesium carbonate, potassium carbonate and sodium carbonate.
In another embodiment of the present invention is disclosed a process for preparing a compound of formula (V) using a second solvent selected from dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide and mixtures thereof In another embodiment of the present invention is disclosed a process for preparing a compound of formula (V) wherein step (b) is conducted at about 15xc2x0 C. to about 50xc2x0 C.
In another embodiment of the present invention is disclosed a process for preparing a compound of formula (V) wherein step (b) is conducted for a period of about 24 hours to about 168 hours.
In another embodiment of the present invention is disclosed a process for preparing a compound of formula (V) wherein the acid is para-toluenesulfonic acid monohydrate; the first solvent is tetrahydrofaran:2-methoxyethanol in about a (1:1) ratio; step (a) is conducted at about 50xc2x0 C. to about 80xc2x0 C. and step (a) is conducted for a period of about 12 hours to about 48 hours.
In another embodiment of the present invention is disclosed a process for preparing a compound of formula (V) wherein the acid is para-toluenesulfonic acid monohydrate; the first solvent is tetrahydrofuran:2-methoxyethanol in about a (1:1) ratio; step (a) is conducted at about 50xc2x0 C. to about 80xc2x0 C., step (a) is conducted for a period of about 12 hours to about 48 hours; the base is cesium carbonate; the second solvent is dimethylacetamide; step (b) is conducted at about 18xc2x0 C. to about 23xc2x0 C.; and step (b) is conducted for a period of about 48 hours to about 168 hours.
As used throughout this specification and the appended claims, the following terms have the following meanings.
The term xe2x80x9calkenyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 1,1-dimethyl-3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and 3-decenyl.
The term xe2x80x9calkenyloxy,xe2x80x9d as used herein, refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkenyloxy include, but are not limited to, allyloxy, 2-butenyloxy and 3-butenyloxy.
The term xe2x80x9calkenyloxyalkyl,xe2x80x9d as used herein, refers to a alkenyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkenyloxyalkyl include, but are not limited to, (allyloxy)methyl, (2-butenyloxy)methyl and (3-butenyloxy)methyl.
The term xe2x80x9calkenyloxy(alkenyloxy)alkyl,xe2x80x9d as used herein, refers to 2 independent alkenyloxy groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkenyloxy(alkenyloxy)alkyl include, but are not limited to, 1,2-bis(allyloxy)ethyl and 1,1-bis[(allyloxy)methyl]propyl.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.
The term xe2x80x9calkoxyalkyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl and 1,1-dimethyl-3-(methoxy)propyl.
The term xe2x80x9calkoxycarbonyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.
The term xe2x80x9calkoxycarbonylalkyl,xe2x80x9d as used herein, refers to an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl and 1,1-dimethyl-2-(methoxycarbonyl)ethyl.
The term xe2x80x9calkoxycarbonyl(halo)alkyl,xe2x80x9d as used herein, refers to an alkoxycarbonyl group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxycarbonyl(halo)alkyl include, but are not limited to, 1,1-dichloro-2-methoxy-2-oxoethyl, 1,1-difluoro-2-methoxy-2-oxoethyl, 1,1-dichloro-3-methoxy-3-oxopropyl and 1,1-difluoro-3-methoxy-3-oxopropyl.
The term xe2x80x9calkoxy(halo)alkyl,xe2x80x9d as used herein, refers to an alkoxy group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxy(halo)alkyl include, but are not limited to, dichloro(methoxy)methyl, dichloro(ethoxy)methyl, dichloro(tert-butoxy)methyl, 1,1-dichloro-2-ethoxyethyl, 1,1-dichloro-2-methoxyethyl, 1,1-dichloro-3-methoxypropyl and 1,2-dichloro-3-methoxypropyl.
The term xe2x80x9calkoxysulfonyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl and ethoxysulfonyl.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 1-ethylpropyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
The term xe2x80x9calkylcarbonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.
The term xe2x80x9calkylcarbonylalkyl,xe2x80x9d as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 1,1-dimethyl-3-oxobutyl, 3-oxobutyl and 3-oxopentyl.
The term xe2x80x9calkylcarbonyl(halo)alkyl,xe2x80x9d as used herein, refers to an alkylcarbonyl group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonyl(halo)alkyl include, but are not limited to, 1,1-dichloro-2-oxopropyl, 1,1-dichloro-3-oxobutyl, 1,1-difluoro-3-oxobutyl and 1,1-dichloro-3-oxopentyl.
The term xe2x80x9calkylcarbonyloxy,xe2x80x9d as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy and ethylcarbonyloxy.
The term xe2x80x9calkylcarbonyloxyalkyl,xe2x80x9d as used herein, refers to an alkylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonyloxyalkyl include, but are not limited to, acetyloxymethyl and 2-(ethylcarbonyloxy)ethyl.
The term xe2x80x9calkylenexe2x80x9d or xe2x80x9calkylene bridgexe2x80x9d refers to a divalent group derived from a straight chain hydrocarbon of from 1 to 3 carbon atoms. Representative examples of alkylene or alkylene bridge include, xe2x80x94CH2xe2x80x94 xe2x80x94CH2CH2xe2x80x94, and xe2x80x94CH2CH2CH2xe2x80x94.
The term xe2x80x9calkylsulfinyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl and ethylsulfinyl.
The term xe2x80x9calkylsulfinylalkyl,xe2x80x9d as used herein, refers to an alkylsulfinyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylsulfinylalkyl include, but are not limited to, methylsulfinylmethyl and ethylsulfinylmethyl.
The term xe2x80x9calkylsulfonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
The term xe2x80x9calkylsulfonylalkyl,xe2x80x9d as used herein, refers to an alkylsulfonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylsulfonylalkyl include, but are not limited to, methylsulfonylmethyl and ethylsulfonylmethyl.
The term xe2x80x9calkylthio,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited to, methylsulfanyl, ethylsulfanyl, propylsulfanyl, 2-propylsulfanyl and tert-butylsulfanyl.
The term xe2x80x9calkylthioalkyl,xe2x80x9d as used herein, refers to an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylthioalkyl include, but are not limited to, tert-butylsulfanylmethyl, 2-ethylsulfanylethyl, 2-methylsulfanylethyl and methylsulfanylmethyl.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and 1-butynyl.
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings.
Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl and fluorenyl.
The aryl groups of this invention may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl, alkoxysulfonyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl, carboxy, cyano, halo, haloalkyl, haloalkoxy, nitro, oxo, sulfamyl, sulfamylalkyl, xe2x80x94NRARB, (NRARB)alkyl, (NRARB)carbonyl, (NRARB)carbonylalkyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl and quinolinyl wherein said furyl, imidazolyl, isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, and quinolinyl may be substituted with 1, 2 or 3 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl, alkoxysulfonyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl, cyano, halo, haloalkyl, haloalkoxy, nitro, sulfamyl, sulfamylalkyl, xe2x80x94NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)carbonylalkyl as defined herein.
The term xe2x80x9carylalkoxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy and 5-phenylpentyloxy.
The term xe2x80x9carylalkoxyalkyl,xe2x80x9d as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkoxyalkyl include, but are not limited to, 2-phenylethoxymethyl, 2-(3-naphth-2-ylpropoxy)ethyl and 5-phenylpentyloxymethyl.
The term xe2x80x9carylalkoxycarbonyl,xe2x80x9d as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl and naphth-2-ylmethyloxycarbonyl.
The term xe2x80x9carylalkoxycarbonylalkyl,xe2x80x9d as used herein, refers to an arylalkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkoxycarbonylalkyl include, but are not limited to, benzyloxycarbonylmethyl, 2-(benzyloxycarbonyl)ethyl and 2-(naphth-2-ylmethyloxycarbonyl)ethyl.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 1,1-dimethyl-2-phenylethyl, 3-phenylpropyl and 2-naphth-2-ylethyl.
The term xe2x80x9carylalkylthio,xe2x80x9d as used herein, refers to an arylalkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of arylalkylthio include, but are not limited to, 2-phenylethylthio, 3-naphth-2-ylpropylthio and 5-phenylpentylthio.
The term xe2x80x9carylalkylthioalkyl,xe2x80x9d as used herein, refers to an arylalkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkylthioalkyl include, but are not limited to, 2-phenylethylsulfanylmethyl, 3-naphth-2-ylpropylsulfanylmethyl and 2-(5-phenylpentylsulfanyl)ethyl.
The term xe2x80x9carylcarbonyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and naphthoyl.
The term xe2x80x9carylcarbonylalkyl,xe2x80x9d as used herein, refers to an arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylcarbonylalkyl include, but are not limited to, 2-oxo-3-phenylpropyl and 1,1-dimethyl-3-oxo-4-phenylbutyl.
The term xe2x80x9carylcarbonyloxy,xe2x80x9d as used herein, refers to an arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of arylcarbonyloxy include, but are not limited to, benzoyloxy and naphthoyloxy.
The term xe2x80x9carylcarbonyloxyalkyl,xe2x80x9d as used herein, refers to an arylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylcarbonyloxyalkyl include, but are not limited to, benzoyloxymethyl, 2-(benzoyloxy)ethyl and 2-(naphthoyloxy)ethyl.
The term xe2x80x9caryl(halo)alkyl,xe2x80x9d as used herein, refers to an aryl group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aryl(halo)alkyl include, but are not limited to, dichloro(phenyl)methyl, 1,1-dichloro-2-phenylethyl, 1,1-difluoro-2-phenylethyl, 1,1-dichloro-3-phenylpropyl and 1,1-difluoro-3-phenylpropyl.
The term xe2x80x9caryloxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxyphenoxy.
The term xe2x80x9caryloxyalkyl,xe2x80x9d as used herein, refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aryloxyalkyl include, but are not limited to, phenoxymethyl, 2-phenoxyethyl, 3-naphth-2-yloxypropyl and 3-bromophenoxymethyl.
The term xe2x80x9caryloxycarbonyl,xe2x80x9d as. used herein, refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of aryloxycarbonyl include, but are not limited to, phenoxycarbonyl and naphthyloxycarbonyl.
The term xe2x80x9caryloxycarbonylalkyl,xe2x80x9d as used herein, refers to an aryloxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aryloxycarbonylalkyl include, but are not limited to, phenoxycarbonylmethyl, 2-(phenoxycarbonyl)ethyl and naphthyloxycarbonyl.
The term xe2x80x9carylsulfonyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of arylsulfonyl include, but are not limited to, naphthylsulfonyl, phenylsulfonyl and 4-fluorophenylsulfonyl.
The term xe2x80x9carylsulfonylalkyl,xe2x80x9d as used herein, refers to an arylsulfonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylsulfonylalkyl include, but are not limited to, 1,1-dimethyl-3-(phenylsulfonyl)propyl, naphthylsulfonylmethyl, 2-(phenylsulfonyl)ethyl, phenylsulfonylmethyl and 4-fluorophenylsulfonylmethyl.
The term xe2x80x9carylthio,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of arylthio include, but are not limited to, phenylsulfanyl, naphth-2-ylsulfanyl and 5-phenylhexylsulfanyl.
The term xe2x80x9carylthioalkyl,xe2x80x9d as used herein, refers to an arylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylthioalkyl include, but are not limited to, phenylsulfanylmethyl, 2-naphth-2-ylsulfanylethyl and 5-phenylhexylsulfanylmethyl.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)xe2x80x94 group.
The term xe2x80x9ccarboxy,xe2x80x9d as used herein, refers to a xe2x80x94CO2H group.
The term xe2x80x9ccarboxyalkyl,xe2x80x9d as used herein, refers to a carboxy group, as defined herenin appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl and 3-carboxy-1,1-dimethylpropyl.
The term xe2x80x9ccarboxy(halo)alkyl,xe2x80x9d as used herein, refers to a carboxy group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxy(halo)alkyl include, but are not limited to, carboxy(dichloro)methyl, carboxy(difluoro)methyl, 2-carboxy-1,1-dichloroethyl and 2-carboxy-1,1-difluoroethyl.
The term xe2x80x9ccyano,xe2x80x9d as used herein, refers to a xe2x80x94CN group.
The term xe2x80x9ccyanoalkyl,xe2x80x9d as used herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 3-cyano-1,1-dimethylpropyl and 3-cyano-1,1-diethylpropyl.
The term xe2x80x9ccyano(halo)alkyl,xe2x80x9d as used herein, refers to a cyano group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyano(halo)alkyl include, but are not limited to, 3-cyano-1,1-difluoropropyl, 1,1-dichloro-3-cyanopropyl and 3-cyano-1,1-bis(trifluoromethyl)propyl.
The term xe2x80x9ccycloalkenyl,xe2x80x9d as used herein, refers to a cyclic hydrocarbon containing from 3 to 8 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of cycloalkenyl include, but are not limited to, cyclohexene, 1-cyclohexen-2-yl, 3,3-dimethyl-1-cyclohexene, cyclopentene and cycloheptene.
The cycloalkenyl groups of this invention can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkynyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, sulfamylalkyl, xe2x80x94NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)carbonylalkyl.
The term xe2x80x9ccycloalkenylalkyl,xe2x80x9d as used herein, refers to a cycloalkenyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkenylalkyl include, but are not limited to, (2,6,6-trimethyl-1-cyclohexen-1-yl)methyl, 1-cyclohexen-1-ylmethyl and 2-(2-cyclohepten-1-yl)ethyl.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ring systems are exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane. Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.03,7]nonane and tricyclo[3.3.1.13,7]decane (adamantane).
The cycloalkyl groups of this invention can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfonylalkyl, alkynyl, alkylcarbonyloxy, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonylalkyl, cyanoalkyl, cycloalkylalkyl, halo, haloalkoxy, haloalkyl, heterocyclealkyl, hydroxy, hydroxyalkyl, sulfamylalkyl, xe2x80x94NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)carbonylalkyl.
The term xe2x80x9ccycloalkylalkoxy,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of cycloalkylalkoxy include, but are not limited to, cyclopropylmethoxy, 2-cyclobutylethoxy, cyclopentylmethoxy, cyclohexylmethoxy and 4-cycloheptylbutoxy.
The term xe2x80x9ccycloalkylalkoxyalkyl,xe2x80x9d as used herein, refers to a cycloalkylalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkoxyalkyl include, but are not limited to, cyclopropylmethoxymethyl, 2-cyclobutylethoxymethyl, cyclopentylmethoxymethyl, 2-cyclohexylethoxymethyl and 2-(4-cycloheptylbutoxy)ethyl.
The term xe2x80x9ccycloalkylalkyl,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl.
The term xe2x80x9ccycloalkylcarbonyl,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl and cyclohexylcarbonyl.
The term xe2x80x9ccycloalkyloxy,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of cycloalkyloxy include, but are not limited to, cyclohexyloxy and cyclopentyloxy.
The term xe2x80x9ccycloalkyloxyalkyl,xe2x80x9d as used herein, refers to a cycloalkyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkyloxyalkyl include, but are not limited to, 4-(cyclohexyloxy)butyl and cyclohexyloxymethyl.
The term xe2x80x9ccycloalkylalkylthio,xe2x80x9d as used herein, refers to a cycloalkylalkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of cycloalkylalkylthio include, but are not limited to, (2-cyclohexylethyl)sulfanyl and cyclohexylmethylsulfanyl.
The term xe2x80x9ccycloalkylalkylthioalkyl,xe2x80x9d as used herein, refers to a cycloalkylalkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkylthioalkyl include, but are not limited to, 2-[(2-cyclohexylethyl)sulfanyl]ethyl and (2-cyclohexylethyl)sulfanylmethyl.
The term xe2x80x9ccycloalkylthio,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of cycloalkylthio include, but are not limited to, cyclohexylsulfanyl and cyclopentylsulfanyl.
The term xe2x80x9ccycloalkylthioalkyl,xe2x80x9d as used herein, refers to a cycloalkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylthioalkyl include, but are not limited to, 4-(cyclohexylsulfanyl)butyl and cyclohexylsulfanylmethyl.
The term xe2x80x9cformyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)H group.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogen,xe2x80x9d as used herein, refers to xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or xe2x80x94F.
The term xe2x80x9chaloalkoxy,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, 1,2-difluoroethoxy, trifluoromethoxy and pentafluoroethoxy.
The term xe2x80x9chaloalkenyl,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein. Representative examples of haloalkenyl include, but are not limited to, 2,2-dichloroethenyl, 2,2-difluoroethenyl and 5-chloropenten-2-yl.
The term xe2x80x9chaloalkyl,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, trichloromethyl, 1,1-dichloroethyl, 2-fluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoro-1-(trifluoromethyl)-1-(methyl)ethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.
The term xe2x80x9chaloalkylcarbonyl,xe2x80x9d as used herein, refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of haloalkylcarbonyl include, but are not limited to, chloromethylcarbonyl, trichloromethylcarbonyl and trifluoromethylcarbonyl.
The term xe2x80x9chaloalkylsulfonyl,xe2x80x9d as used herein, refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of haloalkylsulfonyl include, but are not limited to, chloromethylsulfonyl, trichloromethylsulfonyl and trifluoromethylsulfonyl.
The term xe2x80x9chaloalkynyl,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkynyl group, as defined herein. Representative examples of haloalkynyl include, but are not limited to and 4,4,4-trichlorobutyn-2-yl.
The term xe2x80x9cheterocycle,xe2x80x9d as used herein, refers to a monocyclic or a bicyclic ring system. Monocyclic ring systems are exemplified by any 5 or 6 membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6-membered ring has from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, azepinyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, 1,3-dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, thiomorpholine sulfone, thiopyranyl, triazinyl, triazolyl and trithianyl. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzotriazolyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, indazolyl, indolyl, indolinyl, indolizinyl, naphthyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoindolinyl, 1-isoindolinonyl, isoquinolinyl, 1-isoquinolinonyl, phthalazinyl, pyranopyridinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl and thiopyranopyridinyl.
The heterocycle groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl, alkoxysulfonyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl, carboxy, cyano, halo, haloalkyl, haloalkoxy, nitro, oxo, sulfamyl, sulfamylalkyl, xe2x80x94NRARB, (NRARB)alkyl, (NRARB)carbonyl, (NRARB)carbonylalkyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, and quinolinyl wherein said furyl, imidazolyl, isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothilazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl and quinolinyl may be substituted with 1 or 2 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl, alkoxysulfonyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl, carboxy, cyano, halo, haloalkyl, haloalkoxy, nitro, sulfamyl, sulfamylalkyl, xe2x80x94NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)carbonylalkyl.
The term xe2x80x9cheterocyclealkoxy,xe2x80x9d as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of heterocyclealkoxy include, but are not limited to, 2-pyrid-3-ylethoxy, 3-quinolin-3-ylpropoxy and 5-pyrid-4-ylpentyloxy.
The term xe2x80x9cheterocyclealkoxyalkyl,xe2x80x9d as used herein, refers to a heterocyclealkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkoxyalkyl include, but are not limited to, 2-pyrid-3-ylethoxymethyl, 2-(3-quinolin-3-ylpropoxy)ethyl and 5-pyrid-4-ylpentyloxymethyl.
The term xe2x80x9cheterocyclealkyl,xe2x80x9d as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, pyrid-3-ylmethyl and pyrimidin-5-ylmethyl.
The term xe2x80x9cheterocyclealkylthio,xe2x80x9d as used herein, refers to a heterocyclealkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of heterocyclealkylthio include, but are not limited to, 2-pyrid-3-ylethysulfanyl, 3-quinolin-3-ylpropysulfanyl and 5-pyrid-4-ylpentylsulfanyl.
The term xe2x80x9cheterocyclealkylthioalkyl,xe2x80x9d as used herein, refers to a heterocyclealkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkylthioalkyl include, but are not limited to, 2-pyrid-3-ylethysulfanylmethyl, 2-(3-quinolin-3-ylpropysulfanyl)ethyl and 5-pyrid4-ylpentylsulfanylmethyl.
The term xe2x80x9cheterocyclecarbonyl,xe2x80x9d as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocyclecarbonyl include, but are not limited to, pyrid-3-ylcarbonyl, quinolin-3-ylcarbonyl and thiophen-2-ylcarbonyl.
The term xe2x80x9cheterocycleoxy,xe2x80x9d as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of heterocycleoxy include, but are not limited to, pyrid-3-yloxy and quinolin-3-yloxy.
The term xe2x80x9cheterocycleoxyalkyl,xe2x80x9d as used herein, refers to a heterocycleoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocycleoxyalkyl include, but are not limited to, pyrid-3-yloxymethyl and 2quinolin-3-yloxyethyl.
The term xe2x80x9cheterocyclethio,xe2x80x9d as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of heterocyclethio include, but are not limited to, pyrid-3-ylsulfanyl and quinolin-3-ylsulfanyl.
The term xe2x80x9cheterocyclethioalkyl,xe2x80x9d as used herein, refers to a heterocyclethio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclethioalkyl include, but are not limited to, pyrid-3-ylsulfanylmethyl and 2-quinolin-3-ylsulfanylethyl.
The term xe2x80x9chydroxy,xe2x80x9d as used herein, refers to an xe2x80x94OH group.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, refers to 1 or 2 hydroxy groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-ethyl-4-hydroxyheptyl, 2-hydroxy-1, -dimethylethyl and 3-hydroxy-1,1-dimethylpropyl.
The term xe2x80x9clower alkyl,xe2x80x9d as used herein, is a subset of alkyl as defined herein and refers to a straight or branched chain hydrocarbon group containing from 1 to 6 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl.
The term xe2x80x9cmercapto,xe2x80x9d as used herein, refers to a xe2x80x94SH group.
The term xe2x80x9cmercaptoalkyl,xe2x80x9d as used herein, refers to a mercapto group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of mercaptoalkyl include, but are not limited to, 2-sulfanylethyl and 3-sulfanylpropyl.
The term xe2x80x9cxe2x80x94NR9R10,xe2x80x9d as used herein, refers to two groups, R9 and R10, which are appended to the parent molecular moiety through a nitrogen atom. R9 and R10 are independently selected from hydrogen, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl, as defined herein. Representative examples of xe2x80x94NR9R10 include, but are not limited to, acetylamino, amino, methylamino, (ethylcarbonyl)methylamino, ethylmethylamino, formylamino, methylsulfonylamino and phenylsulfonylamino.
The term xe2x80x9c(NR9R10)alkyl,xe2x80x9d as used herein, refers to a xe2x80x94NR9R10 group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NR9R10)alkyl include, but are not limited to, acetylaminomethyl, aminomethyl, 2-aminoethyl, 2-(methylamino)ethyl, (ethylcarbonyl)methylaminomethyl, 3-(ethylmethylamino)propyl, 1,1-dimethyl-3-(dimethylamino)propyl, 2-(formylamino)ethyl, methylsulfonylaminomethyl, 2-(phenylsulfonylamino)ethyl and benzylsulfonylaminomethyl.
The term xe2x80x9c(NR9R10)carbonyl,xe2x80x9d as used herein, refers to a xe2x80x94NR9R10 group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NR9R10)carbonyl include, but are not limited to, aminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl and benzylaminocarbonyl.
The term xe2x80x9c(NR9R10)carbonylalkyl,xe2x80x9d as used herein, refers to a (NR9R10)carbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NR9R10)carbonylatkyl include, but are not limited to, aminocarbonylmethyl, dimethylaminocarbonylmethyl, 2-(ethylaminocarbonyl)ethyl and 3-(benzylaminocarbonyl)propyl.
The term xe2x80x9cxe2x80x94NRARB,xe2x80x9d as used herein, refers to two groups, RA and RB, which are appended to the parent molecular moiety through a nitrogen atom. RA and RB are independently selected from hydrogen, alkyl, alkylcarbonyl and formyl, as defined herein. Representative examples ofxe2x80x94NRARB include, but are not limited to, acetylamino, amino, methylamino, (ethylcarbonyl)methylamino, dime thylamino, ethylmethylamino and formylamino.
The term xe2x80x9c(NRARB)alkyl,xe2x80x9d as used herein, refers to a xe2x80x94NRARB group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NRARB)alkyl include, but are not limited to, acetylaminomethyl, aminomethyl, 2-aminoethyl, 2-(methylamino)ethyl, (ethylcarbonyl)methylaminomethyl, 3-(ethylmethylamino)propyl, 1,1-dimethyl-3-(dimethylamino)propyl and 2-(formylamino)ethyl.
The term xe2x80x9c(NRARB)carbonyl,xe2x80x9d as used herein, refers to a xe2x80x94NRARB group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRARB)carbonyl include, but are not limited to, aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl and diethylaminocarbonyl.
The term xe2x80x9c(NRARB)carbonylalkyl,xe2x80x9d as used herein, refers to a (NRARB)carbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NRARB)carbonylalkyl include, but are not limited to, aminocarbonylmethyl, dimethylaminocarbonylmethyl, 2-(ethylaminocarbonyl)ethyl and 3-(diethylaminocarbonyl)propyl.
The term xe2x80x9cnitro,xe2x80x9d as used herein, refers to a xe2x80x94NO2 group.
The term xe2x80x9coxo,xe2x80x9d as used herein, refers to a (xe2x95x90O) moiety.
The term xe2x80x9coxy,xe2x80x9d as used herein, refers to a (xe2x80x94Oxe2x80x94) moiety.
The term xe2x80x9csulfamyl,xe2x80x9d as used herein, refers to a xe2x80x94SO2NR94R95 group, wherein R94 and R95 are independently selected from hydrogen, alkyl, aryl, and arylalkyl, as defined herein. Representative examples of sulfamyl include, but are not limited to, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, phenylaminosulfonyl and benzylaminosulfonyl.
The term xe2x80x9csulfamylalkyl,xe2x80x9d as used herein, refers to a sulfamyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of sulfamylalkyl include, but are not limited to, (aminosulfonyl)methyl, (dimethylaminosulfonyl)methyl, 2-(aminosulfonyl)ethyl, 3-(aminosulfonyl)propyl and 3-aminosulfonyl-1,1-dimethylpropyl.
The term xe2x80x9csulfamyl(halo)alkyl,xe2x80x9d as used herein, refers to a sulfamyl group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of sulfamyl(halo)alkyl include, but are not limited to, (aminosulfonyl)dichloromethyl, (aminosulfonyl)difluoromethyl, (dimethylaminosulfonyl)difluoromethyl, 2-(aminosulfonyl)-1,1-dichloroethyl, 3-(aminosulfonyl)-1,1-difluoropropyl, 3-aminosulfonyl-1,1-dichloropropyl and 3-(aminosulfonyl)-1,2-difluoropropyl.
The term xe2x80x9csulfinyl,xe2x80x9d as used herein, refers to a xe2x80x94S(O)xe2x80x94 group.
The term xe2x80x9csulfonyl,xe2x80x9d as used herein, refers to a xe2x80x94SO2xe2x80x94 group.
The term xe2x80x9cthio,xe2x80x9d as used herein, refers to a (xe2x80x94Sxe2x80x94) moiety.
Compounds of the present invention may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are xe2x80x9cRxe2x80x9d or xe2x80x9cSxe2x80x9d depending on the configuration of substituents around the chiral carbon atom. The terms xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976,45: 13-30. The present invention contemplates various stereoisomers and mixtures thereof and are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. In particular, the carbon atom attached to R6 and R7 of formula (I-IV), may be individually the (R) enantiomer or individually the (S) enantiomer or a mixture thereof Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
Preferred compounds of the present invention include
3-chloro-N-(1-{[3,4-dioxo-2-(5-pyrimidinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide;
N-(1-{[3,4-dioxo-2-(5-pyrimidinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-difluorobenzamide;
N-(1-{[3,4-dioxo-2-(2-pyrazinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-difluorobenzamide;
3-chloro-N-(1-{[3,4-dioxo-2-(2-pyrazinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide;
3-chloro-N-{1-[(3,4-dioxo-2-{[2-(trifluoromethyl)-3-pyridinyl]amino}-1-cyclobuten-1-yl)amino]-2,2-dimethylpropyl}benzamide;
3-chloro-N-[1-({2-[(2-methoxy-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide;
3,5-difluoro-N-[1-({2-[(2-methoxy-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide;
N-[2,2-dimethyl-1-({2-[(2-methyl-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)propyl]-3,5-difluorobenzamide;
3-chloro-N-{1-[(3,4-dioxo-2-{[4-(trifluoromethyl)-3-pyridinyl]amino}-1-cyclobuten-1-yl)amino]-2,2-dimethylpropyl}benzamide;
3-chloro-N-{1-[(3,4-dioxo-2-{[4-(trifluoromethyl)-3-pyridinyl]amino}-1-cyclobuten-1-yl)amino]-2,2-dimethyl-3-phenylpropyl}benzamide;
3-chloro-N-[1-({2-[(2-methoxy-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethyl-3-phenylpropyl]benzamide;
3-chloro-N-{1-[(3,4-dioxo-2-{[2-(trifluoromethyl)-3-pyridinyl]amino}-1-cyclobuten-1-yl)amino]-2,2-dimethyl-3-phenylpropyl}benzamide;
N-[2,2-dimethyl-1-({2-[(4-methyl-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)propyl]-3,5-difluorobenzamide,
3,5-difluoro-N-[1-({2-[(4-methoxy-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3-(3-pyridinyl)propanamide;
3-chloro-N-[1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-(4-pyridinyl)propyl]benzamide;
4-(3-[(3-chlorobenzoyl)amino]-3-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzoic acid,
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)nicotinamide;
5-bromo-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)nicotinamide;
3-{[(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)amino]carbonyl}benzoic acid;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3-(1H-tetraazol-5-yl)benzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3-(3-pyridinyl)benzamide and pharmaceutically acceptable salts thereof
The foregoing compounds, representative of formula (II), may be prepared by one skilled in the art using known synthetic methodology or by using synthetic methodology described in the Schemes and Examples contained herein.
Most preferred compounds of formula (I) include
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)4-methylbenzamide;
4-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-4-iodobenzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-4-(2-furyl)benzamide;
3-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide,
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3-methylbenzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3-fluorobenzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3-iodobenzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,4-dimethylbenzamide;
N-(1-{[3,4-dioxo-2(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,4-dimethoxybenzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino)-2,2-dimethylpropyl)-1-naphthamide;
3,5-dichloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-dimethoxybenzamide;
(xe2x88x92)N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-dimethoxybenzamide;
(+)N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-dimethoxybenzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-difluorobenzamide;
4-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino{-2,2-dimethyl-4-pentenyl)benzamide,
4-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)benzamide;
4-chloro-N-(4-cyano-1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-diethylbutyl)benzamide;
N-(2,2-bis[(allyloxy)methyl]-1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}butyl)-4-chlorobenzamide;
4-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2-ethylbutyl)benzamide;
4-chloro-N-(2-cyclohexyl-1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2-methylpropyl)benzamide;
N-(2-(1-adamantyl)-1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}ethyl)-4-chlorobenzamide;
4-chloro-N-(2,2-dichloro-1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}propyl)benzamide;
3-chloro-N-(2,2-dichloro-1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}propyl)benzamide;
3-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2,3,3,3-pentafluoropropyl)benzamide;
4-chloro-N-(1-{[2-(3-fluoroanilino)-3,4-dioxo-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[2-(4-fluoroanilino)-3,4-dioxo-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-[1-({2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide;
N-[1-({2-[(5-bromo-6-fluoro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]4-chlorobenzamide;
4-chloro-N-[1-({2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)2,2-dimethyl-3-phenylpropyl]benzamide;
N-[1-({2-[(2-chloro-3-pyrdinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]-3-methylbenzamide;
4-chloro-N-(2,2-dimethyl-1-{[(3-pyridinylamino)sulfonyl]amino}propyl)benzamide;
N-(2,2-dimethyl-1-{[(3-pyridinylamino)sulfonyl]amino}propyl)4-iodobenzamide;
N1-{1-[(4-chlorobenzoyl)amino]-2,2-dimethylpropyl}-N2-(3-pyridinyl)ethanediamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3-phenylpropanamide;
N-[1-({2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]-3-(3-pyridinyl)propanamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3-vinylbenzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)[1,1xe2x80x2-biphenyl]-3-carboxamide;
3-acetyl-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-2-pyridinecarboxamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-4-fluoro-3-(trifluoromethyl)benzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-2-phenylacetamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3-phenylprop-2-enamide;
4-chloro-N-(2,2-dichloro-1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}pentyl)benzamide;
4-chloro-N-(1-{[3,4-dioxo-2-(4-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[3,4-dioxo-2-(2-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide;
(+)N-(1-[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-difluorobenzamide;
(xe2x88x92)N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-difluorobenzamide;
N-(2,2-dichloro-1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}propyl)-3,5-difluorobenzamide;
4-chloro-N-{1-[(3,4-dioxo-2-{[5-(trifluoromethyl)pyridin-3-yl]amino}-1-cyclobuten-1-yl)amino]-2,2-dimethylpropyl}benzamide;
3,5-dichloro-N-{1-[(3,4-dioxo-2-{[5-(trifluoromethyl)pyridin-3-yl]amino}-1-cyclobuten-1-yl)amino]-2,2-dimethylpropyl}benzamide;
4-chloro-N-{1-[(3,4-dioxo-2-{[5-(trifluoromethyl)pyridin-3-yl]amino}-1-cyclobuten-1-yl)amino]-2,2-dimethyl-3-penylpropyl}benzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)-3,5-difluorobenzamide;
(+)3-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl) benzamide;
(xe2x88x92) 3-chloro-N-(1-{[3,4dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide;
3,5-dichloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)benzamide;
3-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)benzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)-3-methylbenzamide;
N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethyl-3-phenylpropyl]-3-methylbenzamide;
4-chloro-N-[1-({2-[(6-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide;
4-chloro-N-[1-({2-[(2-fluoropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide;
3-chloro-N-(1-[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-3,3-dimethylbutyl)benzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)thiophene-2-carboxamide;
3-bromo-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide;
3-bromo-N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-9-oxo-9H-fluorene-4-carboxamide;
methyl 3-{[(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)amino]carbonyl}benzoate;
(+)N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3-methylbenzamide;
(xe2x88x92)N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3-methylbenzamide;
(+)N-(1-[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)-3-methylbenzamide;
(xe2x88x92)N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)-3-methylbenzamide;
(+)N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]-3-methylbenzamide;
(xe2x88x92)N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]-3-methylbenzamide;
(+)N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)-3,5-difluorobenzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3-(2-furyl)benzamide;
N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]-3-fluorobenzamide;
3,5-dichloro-N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxocyclobut-1-en-1-yl}amino)-2,2-dimethylpropyl]benzamide;
4-chloro-N-[1-({2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide;
N-[1-({2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]-3-methylbenzamide;
3,5-difluoro-N-[1-({2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide;
N-[1-({2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethyl-3-phenylpropyl]-3-methylbenzamide;
3-chloro-N-[1-({2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide;
N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethyl-3-phenylpropyl]benzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)benzamide;
N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]-3-phenylpropanamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-2-phenoxyacetamide;
N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]-2-phenoxyacetamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-2-methyl-2-phenylpropanarnide;
3-chloro-N-(1-{[3,4-dioxo-2-(pyrazin-2-ylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide;
N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-3,3-dimethylbutyl]benzamide;
3-chloro-N-[1-({2-[(6-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide;
3-chloro-N-{1-[(3,4-dioxo-2-{[6-(trifluoromethyl)pyridin-3-yl]amino}-1-cyclobuten-1-yl)amino]-2,2-dimethylpropyl}benzamide;
3-chloro-N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)isonicotinamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)-3-phenylpropanamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)-2-methyl-2-phenylpropanamide;
N-(1-{[3,4-dioxo2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)-2-phenoxyacetamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)nicotinamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)nicotinamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)isonicotinamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-2-furamide;
N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-pyridin-4-ylpropyl)-3-methylbenzamide;
(xe2x88x92) 3-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)benzamide,
(+) 3-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethyl-3-phenylpropyl)benzamide;
4-chloro-N-({[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}methyl)benzamide;
(+) 3,5-dichloro-N-[(1S)-1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxocyclobut-1-en-1-yl}amino)-2,2-dimethylpropyl]benzamide;
(xe2x88x92) 3,5-dichloro-N-[(1R)-1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxocyclobut-1-en-1-yl}amino)-2,2-dimethylpropyl]benzamide;
(+) N-(1-{[3,4-dioxo-2-(2-chloro3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-difluorobenzamide;
(xe2x88x92) N-(1-{[3,4-dioxo-2-(2-chloro3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-difluorobenzamide and pharmaceutically acceptable salts thereof.
Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: Ac for acetyl, COD for 1,4-cyclooctadiene; DMA for N,N-dimethylacetamide; DMAP for 4-dimethylaminopyridine, DME for dimethoxyethane; DMF for N,N-dimethylformamide; DMSO for dimethylsulfoxide; dppf for 1,1xe2x80x2-bis(diphenylphosphino)ferrocene; Et3N for triethylamine; Et2O for diethyl ether, EtOAc for ethyl acetate; EtOH for ethanol; HPLC for high pressure liquid chromatography, MeOH for methanol; NMP for 1-methyl-2-pyrrolidinone; pyr for pyridine; t-BuOH for tert-butanol; Tf for triflate or xe2x80x94OS(O)2CF3; TFA for trifluoroacetic acid; THF for tetrahydrofuran; and p-TsOH or TsOH for para-toluenesulfonic acid monohydrate.
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds of the invention can be prepared.
The compounds of this invention may be prepared by a variety of synthetic routes. Representative procedures are described in Schemes 1-16. 
A preferred route for preparing aminals of general formula (9), wherein R1, R2, R3, R4, R5 and R6 are as defined in formula (I) is described in Scheme 1. A three-component condensation including benzotriazole, aldehydes of general formula (1), and amides of general formula (2) in the presence of an acid catalyst such as, but not limited to, p-toluenesulfonic acid monohydrate as described in Katritzky, Urogdi, Mayence, J. Org. Chem. (1990), 55, 2206); Katritzky, Chem. Rev. (1998), 98, 409; and Katritzky, J. Heterocyclic Chem. (1996), 33, 1935 provides benzotriazole adducts of general formula (3). Substitution of a bis(ether) precursor of general formula (4), wherein R is alkyl such as, but not limited to, ethyl, with a primary or secondary amine of general formula (5) provides adducts of general formula (6) which can undergo further substitution with ammonia or a primary amine of general formula (7) to provide amines of general formula (8). Benzotriazoles of general formula (3) can be treated with amines of general formula (8) as described in Katritzky, Urogdi, Mayence, J. Org. Chem. (1990), 55, 2206); Katritzky, Chem. Rev. (1998), 98, 409; and Katritzky, J. Heterocyclic Chem. (1996), 33, 1935 in a polar, aprotic solvent such as, but not limited to, DMF in the presence of a base such as, but not limited to, potassium carbonate or cesium carbonate to provide aminals of general formula (9). 
Squarate aminals of general formula (15), wherein R1, R2, R4, and R5 are as defined in formula (I), and R6 is selected from alkyl such as, but not limited to, t-butyl, arylalkyl such as, but not limited to, phenethyl, or haloalkyl such as, but not limited to, xe2x80x94CCl2CH3 or xe2x80x94CF2CF3, can be prepared as described in Scheme 2. Dialkyl squarate esters of general formula (12), wherein R is alkyl, such as, but not limited to, diethyl squarate can be treated with amines of general formula (5) in an alcoholic solvent such as, but not limited to, ethanol as described in Butera, J. Med. Chem. (2000), 43, 1187; and Gilbert, J. Med. Chem. (2000), 43, 1203 to provide squarates of general formula (13). Squarates of general formula (13) can be treated with ammonia in an alcoholic solvent such as, but not limited to, methanol to provide squarates of general formula (14). Benzotriazoles of general formula (3) can be treated with squarates of general formula (14) in a polar, aprotic solvent such as, but not limited to, DMF in the presence of a base such as, but not limited to, cesium carbonate to provide squarate aminals of general formula (15). 
A process for the synthesis of squarate aminals of general formula (15), wherein R1, R2, and R5 are as defined in formula (I), R4 is hydrogen, and R6 is selected from alkyl such as, but not limited to, t-butyl, arylalkyl such as, but not limited to, phenethyl, or haloalkyl such as, but not limited to, xe2x80x94CCl2CH3 or xe2x80x94CF2CF3, can be used as described in Scheme 3. Commercially available 1H-benzotriazole-polystyrene resin (Novabiochem) can be loaded in a three-component condensation including aldehydes of general formula (1), and amides of general formula (2) in the presence of an acid catalyst, but not limited to, p-toluenesulfonic acid monohydrate as described in Katritzky, Belyakov, Tymoshenko, J. Comb. Chem. (1999), 1, 173; and Paio, Zaramella, J. Comb. Chem. (1999), 1, 317 to provide benzotriazole adducts of general formula (18). Benzotriazole adducts of general formula (18) can undergo nucleophilic displacement of the resin bound benzotriazole moiety with squarate amides of general formula (14) in a solvent such as, but not limited to, dimethylacetamide or a cosolvent such as, but not limited to, THF and dimethylacetamide in the presence of a base such as, but not limited to, cesium carbonate to provide aminals of general formula (15).
In the polymer-bound benzotriazole method as described in Scheme 3, the desired components are bound to the resin allowing for efficient purification. In the final product formation, an excess of a squarate of general formula (14) can be used to cleave only the desired products off the resin. The process described in Scheme 3 also offers the potential to create a combinatorial library (array synthesis) of squarate aminals of general formula (15) by enabling diversity at R1, R2, R5,and R6 to be explored. 
Squarate amnials of general formula (15), wherein R1, R2, R4, and R5 are as defined in formula (I) and R6 is halo alkyl such as, but not limited to, xe2x80x94CCl3 or xe2x80x94CF3, can be prepared as described ill Scheme 4. Amides of general formula (2) can be treated with xcex1-haloaldehyde hydrates or xcex1-halohemiacetals of general formula (20), wherein R is hydrogen and Rxe2x80x2 is selected from hydrogen or alkyl, such as, but not limited to, 2,2,2-trichloro-1,1-ethanediol or 1-ethoxy-2,2,2-trifluoro-1-ethanol, followed by addition of a chlorinating agent such as, but not limited to, thionyl chloride and a base such as, but not limited to, pyridine to provide chloroamides of general formula (21). Chloroamides of general formula (21) can be treated with squarates of general formula (14) in a polar, aprotic solvent such as, but not limited to, DMF in the presence of a base such as, but not limited to, cesium carbonate to provide squarate aminals of general formula (15). 
An alternate route for preparing squarate amnials of general formula (15), wherein R1, R2, R5, and R6 are as defined in formula (I) is described in Scheme 5. Squarate aminals of general formula (23), wherein Rxe2x80x3 is alkoxy, can be prepared following the strategy described in Scheme 2. Squarate aminals of general formula (23) can be treated with an acid such as, but not limited to, hydrobromic acid or trifluoroacetic acid to provide primary amines of general formula (24). Amines of general formula (24) can be treated with acid chlorides of general formula (25) in the presence of a base such as, but not limited to, diisopropylethylainine to provide squarate aminals of general formula (15). 
An alternate route for preparing squarate aminals of general formula (15), wherein R1, R2, R4, R5, and R6 are as defined in formula (I) is described in Scheme 6. Compounds of general formula (3) can be treated with ammonia in an alcoholic solvent such as, but not limited to, methanol as described in Katritzky, Urogdi, Mayence, J. Org. Chem. (1990), 55, 2206; Katritzky, Chem. Rev. (1998), 98, 409; and Katritzky; J. Heterocyclic Chem. (1996), 33, 1935 to provide aminoamides of general formula (27). Aminoamides of general formula (27) can be treated with squarates of general formula (13) in alcoholic solvent such as, but not limited to, ethanol or a polar, aprotic solvent such as, but not limited to, acetonitrile to provide squarate aminals of general formula (15). 
Squarate aminals of general formula (15), wherein R1, R2, R4, R5, and R6 are as defined in formula (I), can be prepared as described in Scheme 7. Aminoamides of general formula (27) can be treated with dialkyl squarates of general formula (12), wherein R is alkyl, such as, but not limited to, diethyl squarate in an alcoholic solvent such as, but not limited to, ethanol or a polar, aprotic solvent such as, but not limited to, acetonitrile to provide squarates of general formula (29). Squarates of general formula (29) can be treated with amines of general formula (5) in an alcoholic solvent such as, but not limited to, ethanol to provide squarate aminals of general formula (15). 
Squarate aminals of general formula (15), wherein R1, R2, R4, R5, and R6 are as defined in formula (I), can be prepared as described in Scheme 8. Aminoacetamides of general formula (30) can be treated with acid chlorides of general formula (25) in the presence of a base such as, but not limited to, pyridine or triethylamine to provide the corresponding acylaminoamides of general formula (31). Acylaminoamides of general formula (31) can undergo a Hofmann rearrangement as described in Wallis and Lane, Org. React (1946), 3, 267-306, and references contained therein with reagents such as, but not limited to, iodosobenzene diacetate as described in Loudon et al., Org. Chem. (1984), 49, 4272; Loudon and Boutin, J. Org. Chem. (1984), 49, 4277, and Chan et al, Synth. Commun. (1988),53, 5158 to provide aminoamides of general formula (27), which can be typically isolated as their hydrochloride salts. Aminoamides of general formula (27) can be treated with squarates of general formula (12), wherein R is alkyl, such as, but not limited to, diethyl squarate in an alcoholic solvent such as, but not limited to, ethanol or a polar, aprotic solvent such as, but not limited to, acetonitrile to provide squarates of general formula (29). Squarates of general formula (29) can then be treated with amines of general formula (5) in an alcoholic solvent such as, but not limited to, ethanol to provide squarate aminals of general formula (15). 
Geminally-substituted squarate aminals of general formula (36), wherein R1, R2, R5, R6, and R7 are as defined in formula (I) and R6=R7 or R6 and R7 taken together with the carbon atom to which they are attached, together form a 5 or 6 membered carbocyclic ring, can be prepared as described in Scheme 9 or as described in Steglich, Chem. Ber. (1974), 107, 1488, and Burger, J. Fluorine Chem. (1982), 20, 813. Primary amides of general formula (2) can be treated with symmetrical ketones of general formula (34) in the presence of a dehydrating agent such as, but not limited to, trifluoroacetic anhydride and a base such as, but not limited to, pyridine to provide symmetrical imines of general formula (35). Symmetrical imines of general formula (35) can be treated with squarates of general formula (14) in the presence of a base such as, but not limited to, triethylamine to provide geminally-substituted squarate aminals of general formula (36). 
Squarate aminals of general formula (38), wherein R1, R2, R3, R4 and R6 are as defined in formula (I) and Rxe2x80x2 is selected from alkoxycarbonyl, aryl, carboxy, heterocycle and xe2x80x94NRARB wherein RA and RB are as defined in formula (I), can be prepared as described in Scheme 10. Squarate aminals of general formula (37), wherein R is Br, I or xe2x80x94OS(O)2CF3, can be treated with a palladium catalyst, a trialkyltin reagent and triphenylarsine in a solvent such as, but not limited to, N-methylpyrrolidin-2-one as described in Farina and Baker, J. Org. Chem. (1990), 55, 5833 to provide aminals of general formula (38). Alternatively, cross-coupling reactions and carbonylations can be done on squarate aminals of general formula (37) using Buchwald, Stille, Suzuki or Heck coupling reaction conditions, all of which are well known to those skilled in the art of organic chemistry. 
Scheme 11 describes a preferred method that provides squarate aminals of general formula (38), wherein R1, R2, R4, and R6 are as defined in formula (I) and Rxe2x80x2 is selected from alkoxycarbonyl, aryl, carboxy, heterocycle and xe2x80x94NRARB wherein RA and RB are as defined in formula (I). Benzotriazole compounds of general formula (40), wherein R is Br, I or xe2x80x94OS(O)2CF3, can be treated with a palladium catalyst, a trialkyltin reagent and triphenylarsine in a solvent such as, but not limited to, N-methylpyrrolidin-2-one as described in Farina and Baker, J. Org. Chem. (1990), 55, 5833 to provide elaborated benzotriazoles of general formula (41). Alternatively, cross-coupling reactions and carbonylations can be done on benzotriazoles of general formula (40) using Buchwald, Stille, Suzuki or Heck coupling reaction conditions all of which are well known to those skilled in the art of organic chemistry. Benzotriazoles of general formula (41) can be treated with squarates of general formula (14) in a polar, aprotic solvent such as, but not limited to, DMF in the presence of a base such as, but not limited to, cesium carbonate to provide squarate aminals of general formula (38). 
Sulfonylamino aminals of general formula (45), wherein R1, R4, R5, and R6 are as defined in formula (I), can be prepared as described in Scheme 12. Primary amines of general formula (42) can be treated with chlorosulfonyl isocyante in the presence of an alcoholic nucleophile such as, but not limited to, t-butanol as described in Abdaoui, Bioorg. Med. Chem. Lett. (1996), 4, 1227 to provide sulfonylamino carbamates of general formula (43). Sulfonylamino carbamates of general formula (43) can be treated with a protic acid such as, but not limited to, trifluoroacetic acid to provide amino sulfonamides of general formula (44). Amino sulfonamides of general formula (44) can be treated with benzotriazoles of general formula (3) in a polar, aprotic solvent such as, but not limited to, DMF in the presence of a base such as, but not limited to, potassium carbonate or cesium carbonate to provide sulfonylamino aminals of general formula (45) 
Ethanediamide aminals of general formula (50), wherein R1, R4, R5, and R6 are as defined in formula (I) can be prepared as described in Scheme 13. Chloroalkyloxalates of general formula (47), wherein R is alkyl, such as, but not limited to, chloroethyloxalate can be treated with primary amines of general formula (42) in the presence of a base such as, but not limited to, triethylamine to provide amidoesters of general formula (48). Amidoesters of general formula (48) can be treated with ammonia in an alcoholic solvent such as, but not limited to, methanol to provide oxalamides of general formula (49). Oxalamides of general formula (49) can be treated with benzotriazoles of general formula (3) in a polar, aprotic solvent such as, but not limited to, DMF in the presence of a base such as, but not limited to, potassium carbonate or cesium carbonate to provide ethanediamide aminals of general formula (50). 
Aminals of general formula (54), wherein R1, R2, R4, R5 and R6 are as defined in formula (I), can be prepared as described in Scheme 14. 3,4-Dichloro-2,5-furandione, purchased from Aldrich Chemical Company, can be treated with amines of general formula (5) as described in previous Schemes to provide furandiones of general formula (52). Furandiones of general formula (52) can be treated with ammonia as described in previous Schemes to provide compounds of general formula (53). Compounds of general formula (53) can be processed as described in Schemes 1-5 and Scheme 9 to provide aminals of general formula (54).
Alternatively, 3,4-dichloro-2,5-furandione can be processed as described in Schemes 6-8 to provide aminals of general formula (54). 
Aminals of general formula (56), wherein R1, R2, R4, R5 and R6 are as defined in formula (I), can be prepared as described in Scheme 15. Pyrrole diones of general formula (55) can be prepared as described in Augustin, Tetrahedron (1980) 36, 1801; and Hanaineh-Abdelnour, Tetrahedron (1999) 55, 11859 and then processed as described in previous Schemes to provide aminals of general formula (56).
Aminals of general formula (5 8), wherein R1, R2, R4, R5 and R6 are as defined in formula (I), can be prepared as described in Scheme 15. Cyclopentene diones of general formula (57) can be prepared as described in Lee et al., JOC (1995) 60, 735; and Yamamoto et al., JACS (1995) 117, 9653 and then processed as described in previous Schemes to provide aminals of general formula (58). 
Squarate aminals of general formula (15), wherein R1, R2, R4, and R5 are as defined in formula (I) and R6 is selected from alkyl such as, but not limited to, t-butyl, arylalkyl such as, but not limited to, phenethyl, or haloalkyl such as, but not limited to, xe2x80x94CCl2CH3 or xe2x80x94CF2CF3, can be prepared as described in Scheme 16. Squaric acid (59) can be treated with oxalyl chloride as described in Ohno et al., J. Chem. Soc., Perkin Trans. 1 (1993), 263; and Yamamoto et al., Tetrahedron (2000), 50, 7783, to provide 3,4-dichloro-cyclobut-3-ene-1,2-dione (60) which can be treated with alcohols such as, but not limited to, methanol as described in Ohno et al., J. Chem. Soc., Perkin Trans. 1(1993), 263, to provide compounds of general formula (61) wherein R is alkyl. Compounds of general formula (61) can be treated with amines of general formula (5) in the presence of a base such as, but not limited to, sodium bicarbonate in a polar aprotic solvent such as, but not limited to, DMF, to provide squarates of general formula (13). Squarates of general formula (13) can be treated with ammonia in an alcoholic solvent such as, but not limited to, methanol to provide squarates of general formula (14). Benzotriazoles of general formula (3) can be treated with squarates of general formula (14) in a polar, aprotic solvent such as, but not limited to, DMF in the presence of a base such as, but not limited to, cesium carbonate to provide squarate aminals of general formula (15).